National Cancer Institute

Posted Date: Apr 27, 2014

Expert-reviewed information summary about the genetics of endocrine and neuroendocrine neoplasias. This summary contains information about the MEN1 gene, the RET gene, genetic testing, and clinical interventions. Psychosocial issues associated with genetic testing and counseling of individuals who may have a hereditary medullary thyroid cancer syndrome are also discussed.

Genetics of Endocrine and Neuroendocrine Neoplasias

Introduction

Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.

Many of the genes described in this summary are found in the Online Mendelian Inheritance in Man (OMIM) database. When OMIM appears after a gene name or the name of a condition, click on OMIM for a link to more information.

There are several hereditary syndromes that involve endocrine or neuroendocrine glands, such as multiple endocrine neoplasia type 1 (MEN1), multiple endocrine neoplasia type 2 (MEN2), pheochromocytoma, paraganglioma, and von Hippel-Lindau syndrome. This summary currently focuses on MEN1, MEN2, and familial paraganglioma. Von Hippel-Lindau syndrome is discussed in the Genetics of Kidney Cancer summary.

The term multiple endocrine neoplasia is used to describe a group of heritable tumors of endocrine tissues that may be benign or malignant. They are typically classified into two main categories: MEN1 and MEN2. The tumors usually manifest themselves by overproduction of hormones, tumor growth, or both.

Comprising varying combinations of more than 20 endocrine and nonendocrine tumors, MEN1 may be a difficult syndrome to define clinically. In general, however, MEN1 is characterized by tumors of the parathyroids, pancreas, and pituitary gland. This syndrome may also include carcinoid tumors, adrenocortical tumors, and nonendocrine tumors, such as facial angiofibromas, collagenomas, lipomas, meningiomas, ependymomas, and leiomyomas.

MEN1 syndrome, also known as Wermer syndrome, results from a mutation in the MEN1 gene. It has a prevalence of about 1 in 30,000 individuals.

MEN2 is caused by a mutation in the RET proto-oncogene. Historically, MEN2 has been further stratified into the following three subtypes based on the presence or absence of certain endocrine tumors in the individual or family:

All three subtypes of MEN2 (MEN2A, FMTC, and MEN2B) impart a high risk of developing medullary thyroid cancer (MTC). MEN2A has an increased risk of pheochromocytoma and parathyroid adenoma and/or hyperplasia. MEN2B has an increased risk of pheochromocytoma and includes additional clinical features, such as mucosal neuromas of the lips and tongue, distinctive faces with enlarged lips, ganglioneuromatosis of the gastrointestinal tract, and an asthenic Marfanoid body habitus. FMTC has been defined as the presence of at least four individuals with MTC without any other signs or symptoms of pheochromocytoma or hyperparathyroidism in the proband or other family members.

Some families previously classified as having FMTC will go on to develop one or more of the MEN2A-related tumors, suggesting that FMTC is simply a milder variant of MEN2A. Offspring of affected individuals have a 50% chance of inheriting the RET gene mutation.

The age at onset of MTC is different for each subtype of MEN2. MTC typically occurs during early childhood in patients with MEN2B, predominantly during early adulthood in patients with MEN2A, and during middle-age in patients with FMTC.

Germline DNA-based testing of the RET gene (chromosomal region 10q11.2) identifies disease-causing mutations in more than 95% of individuals with MEN2A and MEN2B and in about 88% of individuals with FMTC.

The prevalence of MEN2 has been estimated to be between 1 in 30,000 and 1 in 35,000 individuals. The vast majority of MEN2 cases are MEN2A. In the United States, an estimated 472 cases of MEN2-related MTC are diagnosed per year.

Paragangliomas (PGLs) and pheochromocytomas are rare tumors arising from chromaffin cells, which have the ability to synthesize, store, and secrete catecholamines and neuropeptides. In 2004, the World Health Organization characterized pheochromocytomas as tumors arising in the adrenal gland. PGLs may occur sporadically, as a manifestations of a hereditary syndrome, or as the sole tumor in hereditary PGL/pheochromocytoma syndrome.

Multiple Endocrine Neoplasia Type 1

Clinical Description

Multiple endocrine neoplasia type 1 (MEN1) ( OMIM) is an autosomal dominant syndrome, with an estimated incidence in the general population of 1 to 2 cases per 100,000. The major endocrine features of MEN1 include the following:

Parathyroid tumors and primary hyperparathyroidism (PHPT).

Duodenopancreatic neuroendocrine tumors (NETs).

Pituitary tumors.

A diagnosis of MEN1 is made when an individual has two of these three major endocrine tumors. Familial MEN1 is defined as at least one MEN1 case plus at least one first-degree relative with one of these three tumors. The age-related penetrance of MEN1 is 45% at age 30 years, 82% at age 50 years, and 96% at age 70 years.

Parathyroid Tumors and PHPT

The most common features and often the first presenting signs of MEN1 are parathyroid tumors, which result in PHPT. These tumors occur in 80% to 100% of patients by age 50 years. Unlike the solitary adenoma seen in sporadic cases, MEN1-associated parathyroid tumors are typically multiglandular and often hyperplastic. The average age at onset of PHPT in MEN1 is 20 to 25 years, in contrast to that in the general population, which is typically age 50 to 59 years. Parathyroid carcinoma in MEN1 is rare but has been described.

Individuals with MEN1-associated PHPT will have elevated parathyroid hormone (PTH) and calcium levels in the blood. The clinical manifestations of PHPT are mainly the result of hypercalcemia. Mild hypercalcemia may go undetected and have few or no symptoms. More severe hypercalcemia can result in the following:

Since MEN1-associated hypercalcemia is directly related to the presence of parathyroid tumors, surgical removal of these tumors may result in normalization of calcium and PTH levels and relief of symptoms; however, high recurrence rates following surgery have been reported in some series. (Refer to the Interventions section of this summary for more information.)

Duodenopancreatic NETs

Duodenopancreatic NETs are the second most common endocrine manifestation in MEN1, occurring in 30% to 80% of patients by age 40 years. Gastrinomas represent 50% of the gastrointestinal NETs in MEN1 and are the major cause of morbidity and mortality in MEN1 patients. Gastrinomas are usually multicentric, with small (<0.5 cm) foci throughout the duodenum. Most result in peptic ulcer disease (Zollinger-Ellison syndrome), and half are malignant at the time of diagnosis.

Other functioning pancreatic NETs seen in MEN1 include the following:

Insulinomas (10%â20% penetrance).

Vasoactive intestinal peptide tumors (VIPomas) (~1% penetrance).

Glucagonomas (1%â5% penetrance).

Somatostatinomas (~1% penetrance).

Nonfunctioning pancreatic NETs were originally thought to be relatively uncommon tumors in individuals with MEN1, with early penetrance estimates of 20%. With the advent of genetic testing and improved imaging techniques, however, their prevalence in MEN1 has increased, with one study showing a frequency as high as 55% by age 39 years in MEN1 mutation carriers undergoing prospective endoscopic ultrasound of the pancreas. These tumors can be metastatic. One study of 108 MEN1 mutation carriers with nonfunctioning pancreatic NETs showed a positive correlation between tumor size and rate of metastasis and death, with tumors larger than 2 cm having significantly higher rates of metastasis than those smaller than 2 cm. (Refer to the Molecular Genetics of MEN1 section of this summary for more information about MEN1 gene mutations.)

Pituitary Tumors

Approximately 15% to 50% of MEN1 patients will develop a pituitary tumor. Two-thirds are microadenomas (<1.0 cm in diameter), and the majority are prolactin-secreting. Other functioning pituitary tumors can include somatotropinomas and corticotropinomas.

Other MEN1-Associated Tumors

Other manifestations of MEN1 include carcinoids of the foregut (5%â10% of MEN1 patients). These are typically bronchial or thymic and are sometimes gastric. Skin lesions are also common and can include facial angiofibromas (up to 80% of MEN1 patients) and collagenomas (~75% of MEN1 patients). Lipomas (~30% of MEN1 patients) and adrenal cortical lesions (up to 50% of MEN1 patients), including cortical adenomas, diffuse or nodular hyperplasia, or rarely, carcinoma are also common. The following manifestations have also been reported:

Thyroid adenomas.

Pheochromocytoma.

Spinal ependymoma.

Meningioma.

Leiomyoma (e.g., esophageal, lung, and uterine).

Making the Diagnosis of MEN1

MEN1 is often difficult to diagnose in the absence of a significant family history or a positive genetic test for a mutation in the MEN1 gene. One study of 560 individuals with MEN1 showed a significant delay between the time of the first presenting symptom and the diagnosis of MEN1. This may be because some presenting symptoms of MEN1-associated tumors, such as amenorrhea, peptic ulcers, hypoglycemia, and nephrolithiasis, are not specific to MEN1.

Furthermore, identification of an MEN1-associated tumor is not sufficient to make the clinical diagnosis of MEN1 and may not trigger a referral to an endocrinologist. Other studies have shown similar findings, with median time between first presenting symptom and diagnosis of MEN1 ranging from 7.6 years to 12 years. Genetic testing alleviates some of this delay. Several studies have shown statistically significant differences in the age at MEN1 diagnosis between probands and their family members. In one study, clinically symptomatic probands were diagnosed with MEN1 at a mean age of 47.5 years (standard deviation [SD] +/- 13.5 years), while family members were diagnosed at a mean age of 38.5 years (SD +/- 15.4 years; P < .001). In another study of 154 individuals with MEN1, probands were diagnosed at a mean age of 39.5 years (range: 18â74 years), compared with a mean age 27 years (range: 14â56 years; P < .05) in family members diagnosed by predictive genetic testing. These findings underscore the importance of increased awareness of the signs and symptoms of MEN1-related tumors and the constellation of findings necessary to suspect the diagnosis. It also highlights the importance of genetic counseling and testing and communication among family members once a diagnosis of MEN1 is made. Figure 1 illustrates some of the challenges in identifying MEN1 in a family.

Figure 1. MEN1 pedigree. MEN1 can be very difficult to identify in a pedigree. The pedigree on the left was constructed based on self-report, and the pedigree on the right depicts the same family following a review of available medical records. This pedigree shows some of the features of a family with a deleterious mutation across four generations, including affected family members with hyperparathyroidism, a pituitary adenoma, gastrinoma, and a suspected pancreatic tumor. The tumors in MEN1 typically occur at an earlier age than their sporadic counterparts. MEN1 families may exhibit some or all of these features. As an autosomal dominant syndrome, transmission can occur through maternal or paternal lineages, as depicted in the figure.

Since many of the tumors in MEN1 are underdiagnosed or misdiagnosed, identifying an MEN1 gene mutation in the proband early in the disease process can allow for early detection and treatment of tumors and earlier identification of at-risk family members. Many studies have been performed to determine the prevalence of MEN1 gene mutations among patients with apparently sporadic MEN1-related tumors. For example, approximately one-third of patients with Zollinger-Ellison syndrome will carry an MEN1 mutation. In individuals with apparently isolated PHPT or pituitary adenomas, the mutation prevalence is lower, on the order of 2% to 5%, but the prevalence is higher in individuals diagnosed with these tumors before age 30 years. Some authors suggest genetic testing for mutations in MEN1 if one of the following conditions is present:

Gastrinoma at any age.

Multifocal duodenopancreatic NETs at any age.

Parathyroid hyperplasia/adenomas before age 30 or 40 years.

Multiglandular parathyroid adenomas/hyperplasia or recurrent PHPT.

Presence of one of the three main MEN1 tumors plus one of the less common tumors/findings.

Presence of two or more features (e.g., adrenal adenomas and carcinoid tumor).

Molecular Genetics of MEN1

The MEN1 gene is located on chromosome 11q13 and encodes the protein menin. Over 1,300 mutations have been identified in the MEN1 gene to date, and these are scattered across the entire coding region. The majority (~65%) of these are nonsense or frameshift mutations. The remainder are missense mutations (20%), which lead to expression of an altered protein, splice-site mutations (9%), or partial- or whole-gene deletions (1%â4%). There is currently no evidence of genotype-phenotype correlations, and inter- and intra-familial variability is common.

Genetic Testing and Differential Diagnosis

Genetic testing for MEN1 mutations is recommended for individuals meeting clinical diagnostic criteria and may be considered in a subset of the less common tumors. (Refer to the bulleted list in the Making the diagnosis of MEN1 section of this summary for more information.) For individuals meeting diagnostic criteria, the mutation detection rate is approximately 75% to 90% but may be lower in simplex cases. Individuals with isolated parathyroid and/or pituitary tumors are less likely to have an identifiable mutation than those with pancreatic tumors. The majority of commercial laboratories currently offering MEN1 testing use DNA sequencing as their primary method. Several offer additional analysis for partial- or whole-gene deletion and/or duplication, although such mutations are rare and deletion/duplication testing is often reserved for individuals or families in which there is a very high clinical suspicion.

Genetic testing for MEN1 mutations can be used to distinguish between MEN1 and other forms of hereditary hyperparathyroidism, such as familial isolated hyperparathyroidism (FIHP) ( OMIM), hyperparathyroidismâjaw tumor syndrome (HPT-JT), and familial hypocalciuric hypercalcemia (FHH). The hyperparathyroidism in FHH is not primary hyperparathyroidism, which is seen in MEN1, HPT-JT and FIHP. HPT-JT, which is caused by germline mutations in the HRPT2 gene, is associated with PHPT, ossifying lesions of the maxilla and mandible, and renal lesions, usually bilateral renal cysts, hamartomas, and in some cases, Wilms tumor. Unlike MEN1, HPT-JT is associated with an increased risk of parathyroid carcinoma. FIHP, as its name suggests, is characterized by isolated PHPT with no additional endocrine features; in some families, FIHP is the initial diagnosis of what later develops into MEN1, HPT-JT, or FHH. Approximately 20% of families with a clinical diagnosis of FIHP carry germline MEN1 mutations. Mutations in the calcium-sensing receptor (CaSR) gene cause FHH, which can closely mimic the hyperparathyroidism in MEN1. Distinguishing between MEN1 and FHH can be critical in terms of management, as removal of the parathyroid glands in FHH does not correct the patientâs hyperparathyroidism and results in unnecessary surgery without relief of symptoms. Given the differential risks and management of these conditions and the increased risk of parathyroid carcinoma in HPT-JT, genetic diagnosis in a patient presenting with early-onset hyperparathyroidism may play an important role in the management of these patients and their families. Refer to Table 1 for a summary of the clinical features of MEN1 and other forms of hereditary hyperparathyroidism.

Surveillance

Screening and surveillance for MEN1 may employ a combination of biochemical tests and imaging. Available recommendations are summarized in Table 2.

Interventions

Surgical management of MEN1 is complex and controversial, given the multifocal and multiglandular nature of the disease and the high risk of tumor recurrence even after surgery. Establishing the diagnosis of MEN1 prior to making surgical decisions and referring affected individuals to a surgeon with experience in treating MEN1 can be critical in preventing unnecessary surgeries or inappropriate surgical approaches.

Once evidence of parathyroid disease is established biochemically, the recommended course of action is surgical removal of the parathyroids. The timing and the extent of surgery, however, remain controversial. Some groups reserve surgical intervention for symptomatic patients, with continued annual biochemical screening for those who are asymptomatic. Once surgery is necessary, subtotal parathyroidectomy (removal of 3â3.5 glands) is often suggested as the initial treatment. However, the rate of recurrence is quite high (55%â66%), and reoperation is often necessary. Another study has shown that bilateral thymectomy reduces the likelihood of recurrence. Total parathyroidectomy with autotransplantation of parathyroid tissue to the forearm is also an option. A benefit of this approach is the easier removal of recurrent disease from the forearm than from the neck. Although the likelihood of recurrence is lowered by more extensive surgery, this must be weighed against the risk of rendering the patient hypoparathyroid. Management of persistent hypoparathyroidism with oral calcitriol is necessary.

The role of surgery for pancreatic NETs in MEN1 is controversial, given postoperative morbidity, long-term complications, and low cure rates. The timing and extent of surgery depend on many factors, including severity of symptoms, extent of disease, type and location of tumor, risk of metastasis, and patient preference. The primary goal of surgery is to improve long-term survival by reducing symptoms associated with hormone excess and lowering the risk of distant metastasis. While more extensive surgical approaches (e.g., pancreatoduodenectomy) have been associated with higher cure rates and improved overall survival, they also have higher rates of postoperative complications and long-term morbidity. Therefore, the risks and benefits should be carefully considered, and surgical decisions should be made on a case-by-case basis.

Individuals with MEN1 who are diagnosed with NETs often have multiple tumors of various types throughout the pancreas and duodenum, some of which can be identified using magnetic resonance imaging or computed tomography. Many tumors, however, are too small to be detected using standard imaging techniques, and intra-arterial secretin stimulation testing and/or intraoperative ultrasound may be useful. Preoperative assessment using various biochemical and imaging modalities, intraoperative assessment of tumor burden, and resolution of hormonal hyper-secretion are critical and, in some series, have been associated with higher cure rates and longer disease-free intervals.

Medical management of insulinoma using diet and medication is often unsuccessful; the mainstay of treatment for this tumor is surgery. Insulinomas in MEN1 patients can be located throughout the pancreas, with a preponderance found in the distal gland, and have a higher rate of metastasis than sporadic insulinoma. Surgery can range from enucleation of single or multiple large tumors to partial pancreatic resection, or both, to subtotal or total pancreatectomy. More extensive surgical approaches are associated with a lower rate of recurrence but a higher rate of postoperative morbidity. Because insulinoma often occurs in conjunction with nonfunctioning pancreatic tumors, the selective intra-arterial calcium-injection test (SAS test) may be necessary to determine the source of insulin excess. Intraoperative monitoring of insulin/glucose can help determine whether insulin-secreting tumors have been successfully excised.

The majority of MEN1-associated gastrinomas originate in the duodenum. These tumors are typically multifocal and cause hyper-secretion of gastrin, with resultant peptic ulcer disease (Zollinger-Ellison syndrome). The multifocal nature makes complete surgical resection difficult. It is critical to manage symptoms prior to considering any type of surgical intervention. Historically, some groups have recommended close observation of individuals with smaller tumors (<2.0 cm on imaging) who have relief of symptoms using medications (e.g., proton pump inhibitors or histamine-2 agonists); however, this approach may not be optimal for all patients.

Several published series have shown a positive correlation between primary tumor size and rate of distant metastasis. One retrospective study showed that 61% of patients with tumors larger than 3 cm had liver metastases. In another series, 40% of patients with tumors larger than 3 cm had liver metastases. In contrast, both of these series showed significantly lower rates of liver metastases in individuals with tumors smaller than 3 cm (32% and 4.8%, respectively). On the basis of these and other data, many groups recommend surgery in individuals with nonmetastatic gastrinoma who have tumors larger than 2 cm.

The type of surgery for gastrinoma depends on many factors. A Whipple procedure is typically discouraged as an initial surgery, given the high postoperative morbidity and long-term complications, such as diabetes mellitus and malabsorption. Less extensive surgeries have been described with varying results. At a minimum, duodenectomy with intraoperative palpation and/or ultrasound to locate and excise duodenal tumors and peri-pancreatic lymph node dissection are performed. Because most patients with gastrinoma will have concomitant NETs throughout the pancreas, some of which may be nonfunctional, some groups recommend resection of the distal pancreas and enucleation of tumors in the pancreatic head in addition to duodenal tumor excision.

Approximately 50% of individuals with MEN1 will develop nonfunctioning NETs. These are often identified incidentally during assessment and exploration for functioning tumors. As with gastrinomas, the metastatic rate is correlated with larger tumor size; the presence of metastatic disease has been associated with earlier age at death than in those without pancreatic NETs.

Glucagonomas, VIPomas, and somatostatinomas are rare but often have higher rates of malignancy than other pancreatic NETs. These are often treated with aggressive surgery.

Medical therapy to suppress hypersecretion is often the first line of therapy for MEN1-associated pituitary tumors. In one series of 136 patients, medical therapy was successful in approximately one-half of patients with secreting tumors (49 of 116, 42%), and successful suppression was correlated with smaller tumor size. Surgery is often necessary for patients who are resistant to this treatment. Radiation therapy is reserved for patients with incomplete surgical resection.

Multiple Endocrine Neoplasia Type 2

Clinical Description

The endocrine disorders observed in multiple endocrine neoplasia type 2 (MEN2) are medullary thyroid cancer (MTC); its precursor, C-cell
hyperplasia (CCH); pheochromocytoma; and parathyroid adenomas and/or hyperplasia.
MEN2-associated MTC is often bilateral and/or multifocal and arises in the background of CCH. In contrast, sporadic MTC is typically unilateral and/or unifocal. Since approximately 75% to 80% of sporadic cases also have associated CCH, this histopathologic feature cannot be used as a predictor of familial disease. Metastatic spread of MTC to regional lymph nodes (i.e.,
parathyroid, paratracheal, jugular chain, and upper mediastinum) or to distant
sites, such as the liver, is common in patients who
present with a palpable thyroid mass or diarrhea. Although
pheochromocytomas rarely metastasize, they can be clinically significant in cases of intractable
hypertension or anesthesia-induced hypertensive crises. Parathyroid
abnormalities in MEN2 can range from benign parathyroid adenomas or multigland hyperplasia to clinically evident
hyperparathyroidism with hypercalcemia and renal stones.

Historically, individuals and families with MEN2 were classified into one of the following three clinical subtypes based on the presence or absence of certain endocrine tumors in the individual or family:

Current stratification is moving away from a solely phenotype-based classification and more toward one that is based on genotype (i.e., the mutation) and phenotype.

Clinical findings in the three MEN2 subtypes are summarized in Table 3. All three subtypes confer a high risk of MTC; MEN2A and MEN2B confer an increased risk of
pheochromocytoma, and MEN2A has an increased risk of parathyroid hyperplasia
and/or adenoma. Classifying a patient or family by MEN2 subtype is useful in
determining prognosis and management.

MTC and C-Cell Hyperplasia

MTC originates in calcitonin-producing cells (C-cells) of the thyroid gland.
MTC is diagnosed when nests of C-cells extend beyond the basement
membrane and infiltrate and destroy thyroid follicles. CCH
is diagnosed histologically by the presence of an increased number of diffusely
scattered or clustered C-cells. Individuals with RET (REarranged during Transfection) mutations and CCH are at substantially increased risk of progressing to MTC, although such progression is not universal. MTC and CCH
are suspected in the presence of an elevated plasma calcitonin concentration.

A study of 10,864 patients with nodular thyroid disease found 44 (1 of every 250) cases of MTC after stimulation with calcitonin, none of which were clinically suspected. Consequently, half of these patients had no evidence of MTC on fine-needle biopsy and thus might not have undergone surgery without the positive calcitonin stimulation test. CCH associated with a positive calcitonin stimulation test occurs in
about 5% of the general population; therefore, the plasma calcitonin responses to
stimulation do not always distinguish CCH from small MTC and cannot always distinguish between carriers and noncarriers in an MEN2 family.

MTC accounts for 2% to 3% of new cases of thyroid cancer diagnosed annually in
the United States, although this figure may be an underrepresentation of true incidence because of changes in diagnostic techniques. The total number of new cases of MTC diagnosed annually in the United States is
between 1,000 and 1,200, about 75% of which are sporadic (i.e., they
occur in the absence of a family history of either MTC or other endocrine
abnormalities seen in MEN2). The peak incidence of the sporadic form is in the
fifth and sixth decades of life. A study in the
United Kingdom estimated the incidence of MTC at 20 to 25 new cases per year
among a population of 55 million.

In the absence of a positive family
history, MEN2 may be suspected when MTC occurs at an early age or is
bilateral or multifocal. While small series of apparently sporadic MTC cases have suggested a higher prevalence of germline RET mutations, larger series indicate a prevalence range of 1% to 7%. Based on these data, it is widely recommended that RET gene mutation testing be performed for all cases of MTC.

Level of evidence (Screening): 3

Thyroid cancer represents approximately 3% of new malignancies occurring annually in the
United States, with an estimated 62,980 cancer diagnoses and 1,890
cancer deaths per year. Of these cancer diagnoses, 2% to 3% are MTC.

MTC arises from the parafollicular calcitonin-secreting cells of the thyroid
gland. MTC occurs in sporadic and familial forms and may be preceded by
CCH, although CCH is a relatively common abnormality in
middle-aged adults.

Average survival for MTC is lower than that for more common
thyroid cancers (e.g., 83% 5-year survival for MTC compared with 90% to 94% 5-year
survival for papillary and follicular thyroid cancer). Survival is
correlated with stage at diagnosis, and decreased survival in MTC can be
accounted for in part by a high proportion of late-stage diagnosis.

In addition to early stage at diagnosis, other factors associated with improved
survival in MTC include smaller tumor size, younger age at diagnosis, familial
versus sporadic form, and diagnosis by biochemical screening (i.e., screening for
calcitonin elevation) versus symptoms.

A Surveillance, Epidemiology, and End Results population-based study of 1,252 MTC patients found that survival varied by extent of local disease. For example, the 10-year survival rates ranged from 95.6% for those with disease confined to the thyroid gland to 40% for those with distant metastases.

While the majority of MTC cases are sporadic, approximately 20% to 25% are hereditary because of mutations in the RET proto-oncogene. Mutations in the RET gene cause MEN2, an autosomal dominant disorder associated with a high lifetime risk of MTC. Multiple endocrine neoplasia type 1 ( MEN1) ( OMIM) is an autosomal dominant endocrinopathy that is genetically and clinically distinct
from MEN2; however, the similar nomenclature for MEN1 and MEN2 may cause
confusion. There is no increased risk of thyroid cancer for MEN1. (Refer to the MEN1 section of this summary for more information.)

Pheochromocytoma

Pheochromocytomas ( OMIM) arise from the catecholamine-producing chromaffin cells of the adrenal medulla. They are a relatively rare tumor and are suspected among patients with refractory hypertension or
when biochemical screening reveals elevated excretion of catecholamines and
catecholamine metabolites (i.e., norepinephrine, epinephrine, metanephrine, and
vanillylmandelic acid) in 24-hour urine collections or plasma. In the past, measurement of urinary catecholamines was considered the preferred biochemical screening method. However, given that catecholamines are only released intermittently and are metabolized in the adrenal medulla into metanephrine and normetanephrine, the measurement of urine or plasma fractionated metanephrines has become the gold standard. When biochemical screening in an individual who has or is at risk of MEN2 suggests pheochromocytoma, localization studies, such as magnetic resonance imaging (MRI) or computed tomography, can be performed. Confirmation of the diagnosis can be made using I131-metaiodobenzylguanidine scintigraphy or positron emission tomography imaging.

A diagnosis of MEN2 is often considered in individuals with bilateral pheochromocytoma, those with an early age of onset (age <35 years), and those with a personal and/or family history of MTC or hyperparathyroidism. However, MEN2 is not the only genetic disorder that includes a predisposition to pheochromocytoma. Other disorders include neurofibromatosis type 1 (NF1), von Hippel-Lindau disease (VHL), and the hereditary paraganglioma syndromes. A large European consortium that included 271 patients from Germany, 314 patients from France, and 57 patients from Italy (total = 642) with apparently sporadic pheochromocytoma analyzed the known pheochromocytoma/functional paraganglioma susceptibility genes (NF1, RET, VHL, SDHB, and SDHD). The diagnosis of NF1 in this series was made clinically, while all other conditions were diagnosed based on the presence of a germline mutation in the causative gene. The disease was associated with a positive family history in 166 (25.9%) patients; germline mutations were detected in RET (n = 31), VHL (n = 56), NF1 (n = 14), SDHB (n = 34), or SDHD (n = 31). Rigorous clinical evaluation and pedigree analysis either before or after testing revealed that of those with a positive family history and/or a syndromic presentation, 58.4% carried a mutation, compared with 12.7% who were nonsyndromic and/or had no family history. Of the 31 individuals with a germline RET mutation, 28 (90.3%) had a positive family history and/or syndromic presentation, suggesting that most individuals with RET mutations and pheochromocytoma will have a positive family history or other manifestations of the disease.

These data indicate that a significant proportion of individuals presenting with apparently sporadic pheochromocytoma are carriers of germline genetic mutations. Studies have identified additional susceptibility genes that predispose to pheochromocytoma, including TMEM127, MAX, and SDHAF2. Mutations in these genes are thought to account for a small proportion of all hereditary pheochromocytoma. Since testing for mutations in multiple genes in every patient may not be feasible or cost-effective, clinical and genetic screening algorithms have been proposed to assist clinicians in deciding which genes to test and in which order.

Primary Hyperparathyroidism (PHPT)

PHPT is the third most common endocrine disorder in the general population. The incidence increases with age with the vast majority of cases occurring after the sixth decade of life. Approximately 80% of cases are the results of a single adenoma. PHPT can also be seen as a component tumor in several different hereditary syndromes, including the following:

MEN1.

Hyperparathyroidism-Jaw Tumor syndrome.

Familial Isolated Hyperparathyroidism.

MEN2.

Hereditary PHPT is typically multiglandular, presents earlier in life, and can have histologic evidence of both adenoma and glandular hyperplasia.

Clinical Diagnosis of MEN2 Subtypes

The diagnosis of the three MEN2 clinical subtypes relies on a combination of clinical
findings, family history, and molecular genetic testing of the RET gene
(chromosomal region 10q11.2).

MEN2A is diagnosed clinically by the occurrence of two or more specific
endocrine tumors (MTC, pheochromocytoma, or parathyroid adenoma and/or hyperplasia) in
a single individual or in close relatives.

The MEN2A subtype makes up about 60% to 90% of MEN2 cases. The MEN2A subtype
was initially called Sipple syndrome. Since genetic testing for RET
mutations has become available, it has become apparent that about 95% of individuals
with MEN2A will develop MTC; about 50% will develop pheochromocytoma; and
about 15% to 30% will develop hyperparathyroidism.

MTC is generally the first manifestation of MEN2A. In asymptomatic at-risk individuals, stimulation testing may reveal elevated plasma calcitonin
levels and the presence of CCH or MTC. In families with MEN2A,
the biochemical manifestations of MTC generally appear between the ages of 5
and 25 years (mean 15 years). If presymptomatic screening is not performed, MTC
typically presents as a neck mass or neck pain at about age 5 to 20 years.
More than 50% of such patients have cervical lymph node metastases.
Diarrhea, the most frequent systemic symptom, occurs in patients with a plasma
calcitonin level of greater than 10 ng/mL and implies a poor prognosis. Up to
30% of patients with MTC present with diarrhea and advanced disease.

MEN2-associated pheochromocytomas are more often bilateral, multifocal, and associated with extratumoral medullary hyperplasia. They also have an earlier age of onset and are less likely to be malignant than their sporadic counterparts. MEN2-associated pheochromocytomas usually present after MTC, typically with intractable
hypertension.

Unlike the PHPT seen in MEN1, hyperparathyroidism in individuals with MEN2 is typically asymptomatic or associated with only mild elevations in calcium. A series of 56 patients with MEN2-related hyperparathyroidism has been reported by the French Calcitonin Tumors Study Group. The median age at diagnosis was 38 years, documenting that this disorder is rarely the first manifestation of MEN2. This is in sharp contrast to MEN1, in which the vast majority of patients (87%â99%) initially present with primary hyperparathyroidism. Parathyroid abnormalities were found concomitantly with surgery for medullary thyroid carcinoma in 43 patients (77%). Two-thirds of the patients were asymptomatic. Among the 53 parathyroid glands removed surgically, there were 24 single adenomas, four double adenomas, and 25 hyperplastic glands.

A small number of families with MEN2A have pruritic skin lesions known as cutaneous lichen amyloidosis. This lichenoid
skin lesion is located over the upper portion of the back and may appear before
the onset of MTC.

Figure 2 depicts some of the classic manifestations of MEN2A in a family.

The FMTC subtype makes up 5% to 35% of MEN2 cases and is defined as families with four or more cases of MTC in the absence of
pheochromocytoma or parathyroid adenoma/hyperplasia. Families with two or three cases of MTC and incompletely documented screening for
pheochromocytoma and parathyroid disease may actually represent MEN2A; it has been
suggested that these families should be considered unclassified. Misclassification of families with MEN2A as having FMTC (because of too-small family size or later onset of other manifestations of MEN2A) may result in overlooking the risk of pheochromocytoma, a disease with significant morbidity and mortality. For this reason, there is debate about whether FMTC represents a separate entity or is a variation of MEN2A in which there is a lack of or delay in the onset of the other (nonthyroidal) manifestations of the MEN2A syndrome. Some authors recommended, therefore, that patients thought to have pure FMTC also be screened for pheochromocytoma and hyperparathyroidism. (Refer to the Screening of at-risk individuals for pheochromocytoma and Screening of at-risk individuals for hyperparathyroidism sections of this summary for more information.)

MEN2B is diagnosed clinically by the presence of mucosal neuromas of the lips
and tongue, medullated corneal nerve fibers, distinctive facies with
enlarged lips, an asthenic Marfanoid body habitus, and MTC.

The MEN2B subtype makes up about 5% of MEN2 cases. The MEN2B subtype was
initially called mucosal neuroma syndrome or Wagenmann-Froboese syndrome.
MEN2B is characterized by the early development of an aggressive form of MTC
in all patients. Patients with MEN2B who do not undergo thyroidectomy
at an early age (at approximately age 1 year) are likely to develop metastatic MTC at
an early age. Before intervention with early risk-reducing thyroidectomy, the
average age at death in patients with MEN2B was 21 years. Pheochromocytomas
occur in about 50% of MEN2B cases; about half are multiple and often bilateral.
Clinically apparent parathyroid disease is very uncommon. Patients with MEN2B may be identified in infancy or early childhood by a
distinctive facial appearance and the presence of mucosal neuromas on the
anterior dorsal surface of the tongue, palate, or pharynx. The lips become
prominent over time, and submucosal nodules may be present on the vermilion
border of the lips. Neuromas of the eyelids may cause thickening and eversion
of the upper eyelid margins. Prominent thickened corneal nerves may be seen by
slit lamp examination.

About 40% of patients have diffuse ganglioneuromatosis of the gastrointestinal
tract. Associated symptoms include abdominal distension, megacolon,
constipation, and diarrhea.
About 75% of patients have a Marfanoid habitus, often with kyphoscoliosis or
lordosis, joint laxity, and decreased subcutaneous fat. Proximal muscle
wasting and weakness can also be seen.

Genetically Related Disorder

HSCR ( OMIM), a disorder of the enteric plexus of the colon that
typically results in enlargement of the bowel and constipation or obstipation
in neonates, is observed in a small number of individuals with MEN2A, FMTC, or very rarely, MEN2B. Up to 40% of familial cases of HSCR and 3% to 7% of sporadic cases are associated with germline mutations in the RET
proto-oncogene and are designated HSCR1. Some of these RET mutations are
located in codons that lead to the development of MEN2A or FMTC (i.e., codons 609, 618, and 620).

In a study of 44 families, seven families (16%) had cosegregation of MEN2A and HSCR1. The
probability that individuals in a family with MEN2A and an exon 10 Cys
mutation would manifest HSCR1 was estimated to be 6% in one series. Furthermore, in a multicenter international RET mutation consortium study, 6 of a total of 62 kindreds carrying either the C618R or C620R mutation also had HSCR.

A novel analytic approach employing family-based association studies coupled with comparative and functional genomic analysis revealed that a common RET variant within a conserved enhancer-like sequence in intron 1 makes a 20-fold greater contribution to HSCR compared with all known RET mutations. This mutation has low penetrance and different genetic effects in males and females. Transmission to sons and daughters leads to a 5.7-fold and 2.1-fold increase in susceptibility, respectively. This finding is consistent with the greater incidence of HSCR in males. Demonstrating this strong relationship between a common noncoding mutation in RET and the risk of HSCR also accounts for previous failures to detect coding mutations in RET-linked families.

Molecular Genetics of MEN2

MEN2 syndromes are the result of inherited mutations in the RET gene, located on
chromosome region 10q11.2. The RET gene is a proto-oncogene composed of 21
exons over 55 kilobase of genomic material.

RET encodes a receptor tyrosine kinase with extracellular, transmembrane, and
intracellular domains. Details of RET receptor and ligand interaction in this signaling pathway have been reviewed. Briefly, the extracellular domain consists of a calcium-binding
cadherin-like region and a cysteine-rich region that interacts with one of four ligands identified to date. These ligands, e.g., glial-derived neurotropic factor (GDNF), neurturin (NTN), persephin (PSF), and artemin (ATF), also interact with one of four coreceptors in the GFR-alpha family. The tyrosine kinase catalytic core is
located in the intracellular domain, which causes downstream signaling events
through a variety of second messenger molecules. Normal tissues contain
transcripts of several lengths.

MEN2 is a well-defined hereditary cancer syndrome for which genetic testing is considered an important part of the management for at-risk family members. It meets the criteria related to indications for genetic testing for cancer susceptibility outlined by the American Society of Clinical Oncology in its most recent genetic testing policy statement. At-risk individuals are defined as first-degree relatives
(parents, siblings, and children) of a person known to have MEN2. Testing
allows the identification of people with asymptomatic MEN2 who can be offered
risk-reducing thyroidectomy and biochemical screening as preventive measures.
A negative mutation analysis in at-risk relatives, however, is informative only after a disease-causing mutation has been identified in an affected relative. (Refer to the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information.) Because early detection of at-risk individuals affects medical management,
testing of children who have no symptoms is considered beneficial. (Refer to the Genotype-Phenotype Correlations and Risk Stratification section of this summary for more information about clinical management of at-risk individuals.)

Germline DNA testing for RET mutations is generally recommended to all individuals with a diagnosis of MTC, regardless of whether there is a personal or family history suggestive of MEN2. Approximately 95% of patients with MEN2A or MEN2B will have an identifiable germline RET mutation. For FMTC the detection rate is slightly lower at 88%. Importantly, 1% to 7% of apparently sporadic cases of MTC will carry a germline RET mutation, underscoring the importance of testing all cases.

There is no evidence for the involvement of other genetic loci, and all mutation-negative families analyzed to date have demonstrated linkage to the RET gene. For families that do not have a detectable mutation, clinical recommendations can be based on the clinical features in the affected individual and in the family.

There is considerable diversity in the techniques used and the approach to RET mutation testing among the various laboratories that perform this procedure. Methods used to detect mutations in RET include
polymerase chain reaction (PCR) followed by restriction enzyme digestion of PCR products, heteroduplex analysis,
single-stranded conformation polymorphism (SSCP) analysis, denaturing high-performance liquid chromatography (DHPLC), and DNA sequencing. Most testing laboratories, at a minimum, offer testing using a targeted exon approach; that is, the laboratories look for mutations in the exons that are most commonly found to carry mutations (exons 10, 11, 13, 14, 15 and 16). Other laboratories offer testing for all exons. If targeted exon testing in a family with a high clinical suspicion for MEN2 is normal, sequencing of the remaining exons can then be performed.

These differences in mutation detection method and targeted versus full gene testing represent important considerations for selecting a laboratory to perform a test and in interpreting the test result. (Refer to the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information about clinical validity.)

Genotype-Phenotype Correlations and Risk Stratification

Genotype-phenotype correlations in MEN2 are well-established and have long been used to guide clinicians in making medical management recommendations. Several groups have developed mutation-stratification tables based on clinical phenotype, age of onset, and aggressiveness of MTC. This classification strategy was first put forth after the Seventh International Workshop on MEN in 2001, which provided guidelines for the age of genetic testing and prophylactic thyroidectomy. This stratification was revised by the American Thyroid Association (ATA). The original classification scheme provided three levels of risk based on the genetic mutation of an individual. The new guidelines by the ATA added a fourth category for codon 634 mutations, in recognition of their aggressive clinical course. The specific mutations and their ATA classification are summarized in Table 4 and Table 5 below. The ATA's classification scheme has not been prospectively validated as a basis for clinical decision-making.

ATA-level D mutations are the most aggressive and carry the highest risk of developing MTC. These mutations, which are typically seen in MEN2B, are associated with the youngest age at disease onset and the highest risk of mortality. ATA-level C mutations (codon 634) are associated with a slightly lower risk, yet the MTC in patients with these mutations is still quite aggressive and may present at an early age. ATA-level A and level B mutations are associated with a lower risk of aggressive MTC relative to the risk seen in level C and level D mutation carriers. However, the risk of MTC is still substantially elevated over the general population risk and consideration of risk-reducing thyroidectomy is warranted.

A European multicenter study of 207 RET mutation carriers supported previous suggestions that some mutations are associated with early-onset disease. For example, this study found that individuals with the C634Y mutation developed MTC at a significantly younger age (mean 3.2 years; 95% confidence interval [CI], 1.2â5.4) than individuals with the C634R mutation (mean 6.9 years; 95% CI, 4.9â8.8). In the former group of patients, risk-reducing thyroidectomy warrants consideration before the age of 5 years. Although limited by small numbers, the same study did not support a need for risk-reducing thyroidectomy in asymptomatic carriers of mutations in codons 609, 630, 768, 790, 791, 804, or 891 before the age of 10 years or for central lymph node dissection before the age of 20 years. Some authors suggest using these differences as the basis for decisions on the timing of risk-reducing thyroidectomy and the extent of surgery. Others have advocated using basal and stimulated calcitonin levels as a basis for determining the appropriate timing of thyroidectomy.

Mutations 883 and 918 have only been seen in MEN2B and are associated with the earliest age of onset and the most aggressive form of MTC. Approximately 95% of individuals with MEN2B will have the M918T mutation. As discussed above, 50% of individuals with MEN2B will develop pheochromocytoma but PHPT is rare. In addition to mutations at codons 883 and 918, some individuals with a MEN2B-like phenotype have been found to carry two germline mutations. It is likely that as testing for RET becomes more common in clinical practice, additional double mutation phenotypes will be described.

Mutations at codon 634 (ATA-level C) are by far the most frequent finding in families with MEN2A. One study of 477 RET carriers showed that 52.1% had the C634R mutation, 26.0% carried the C634Y mutation, and 9.1% had the C634G mutation. In general, mutations at codon 634 are associated with pheochromocytomas and PHPT. Until recently, MEN2A with cutaneous lichen amyloidosis (CLA) had been seen almost exclusively in patients with mutations at codon 634. However, a recent report described MTC and CLA in an individual previously thought to have FMTC due to a codon 804 mutation. Codon 634 mutations have also been described in FMTC but are almost exclusively C634Y.

In summary, ATA-level D and level C mutations confer the highest risk of MTC (about 95% lifetime risk) with a more aggressive disease course. There is an increased risk of pheochromocytoma (up to 50%). Individuals with codon 634 mutations (but not codon 883 or 918 mutations) also have an increased risk of PHPT.

ATA-level B mutations, located in exon 10 of the RET gene, include mutations at codons 609, 611, 618, 620, and 630. These mutations involve cysteine residues in the extracellular domain of the RET protein and have been seen in families with MEN2A and those with MTC only (FMTC). The risk of MTC in individuals with ATA-level B mutations is approximately 95% to 100%; the risk of pheochromocytoma and hyperparathyroidism is lower than that seen in ATA-level A mutations. In a large series of 518 probands with MTC undergoing RET testing, most individuals with codon 609, 611, 618, 620, or 630 mutations had only MTC and no other features suggestive of MEN2. The authors attributed this to the relatively short follow-up time, incomplete screening of family members, or the method of ascertainment (population-based). Another large study of 390 exon 10 mutation carriers showed an age-related risk of pheochromocytoma for individuals carrying any exon 10 mutation of 23.1% by age 50 years and 33% by age 60 years. Overall prevalence of pheochromocytoma was 17%. This study reported a 3.9% risk of developing hyperparathyroidism by age 60 years.

Individuals with ATA-level A mutations have a lower, albeit still elevated, lifetime risk of MTC. MTC associated with these mutations tends to follow a more indolent course and have a later age at onset, although there are several reports of individuals with ATA-level A mutations who developed MTC before age 20 years. Although pheochromocytoma and PHPT are not commonly associated with level A mutations, they have been described.

In addition to the mutations categorized in Table 4, a number of rare or novel RET mutations have been described. Some of these represent mutations that lead to an FMTC or MEN2 phenotype. Others may represent low penetrance alleles or modifying alleles that confer only a modest risk of developing MTC. Still others may be benign polymorphisms of no clinical significance. A variety of approaches, including segregation analyses, in silico analyses, association studies, and functional assays, can be employed to determine the functional and clinical significance of a given genetic variant. A publicly available RET mutation online database repository was recently developed and includes a complete list of mutations and their associated pathogenicity, phenotype, and other associated clinical information and literature references.

Interventions

Risk-reducing thyroidectomy and parathyroidectomy with reimplantation of one or more parathyroid glands into the neck or nondominant forearm is a
preventiv